Dibenzoxazepine derivative, and pharmaceutical composition comprising the same

ABSTRACT

Dibenzoxazepine derivatives of the formula:  &lt;IMAGE&gt;  wherein R1, n, R2 and R3 are as defined in the description, process for preparing the same, pharmaceutical composition containing the same and method of treating diseases in circulatory organs administering the composition to a patient are disclosed. The compounds of the formula have lipid lowering activity, lipid peroxide lowering activity, blood sugar lowering activity and activity to inhibit the aggregation of platelets, and hence are useful as a medicine.

CROSS-REFERENCES TO RELATED APPLICATION

This application is a continuation-in-part of application Ser. No. 263,184 filed on May 13, 1981, now abandoned.

This invention relates to a dibenzoxazepine derivative of the formula: ##STR2## (wherein R₁ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; n is an integer of 1 or 2 provided that each R₁ may be different when n is 2; R₂ is a hydrogen atom or a lower alkyl group; R₃ is a hydrogen atom, a lower alkyl group, a phenyl group which may have a substituent, or a styryl group which may have a substituent), and a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition containing said dibenzoxazepine derivative as an active ingredient.

According to this invention, the compound of the formula (I) can be obtained easily be cyclizing a compound of the formula (II): ##STR3## (wherein R₁, n, R₂ and R₃ have the same meaning as defined above). The cyclization is performed using an anhydrous inert solvent such as benzene, chloroform, toluene, xylene or chlorobenzene in the presence of a dehydrating agent such as phosphorus oxychloride, zinc chloride, phosphorus pentoxide, polyphosphoric acid or polyphosphoric acid ester at a temperature between 50° and 180° C., preferably between 80° and 130° C., for a period of from 1 to 10 hours, preferably from 3 to 5 hours.

After the cyclization, a compound of the formula (I) wherein R₂ is a lower alkyl group can optionally be hydrolyzed by a conventional method to form carboxylic acid wherein R₂ is a hydrogen.

The compound (II) used as the starting material in the cyclization is also a novel compound, and it can be easily obtained by acylating the corresponding aminodiphenyl ether derivative.

A compound of the formula (I) wherein R₂ is hydrogen is produced on an industrial scale, for example, by oxidizing a compound of the formula (III): ##STR4## (wherein R₁, n and R₂ have the same meaning as defined above). The oxidation is performed in a conventional manner, for example, by dissolving a compound of the formula (III) in an inert solvent such as chloroform, benzene, toluene, xylene or chlorobenzene, and irradiating the solution with light or heating under reflux said compound in the presence of a dehydrogenating agent such as paraquinone or chloranil. The solution is preferably irradiated with natural light or ultraviolet rays for a period of 1 hour to 10 days that varies depending upon the nature and amount of the light used. The reaction using a dehydrogenating agent is performed at a temperature between 50° and 150° C., preferably between 80° and 140° C., for a period of from 1 to 5 hours, preferably from 2 to 4 hours.

The compound of the formula (III) used as the starting material in the oxidation is also a novel compound, and it can readily be prepared by reducing and cyclizing a diphenyl ether (VI) in a solvent such as methanol, ethanol, dioxane or tetrahydrofuran under stirring in the presence of 5 to 10% of a Raney nickel or palladium or carbon at room temperature, optionally followed by hydrolysis. The diphenyl ether (VI) is prepared through the following reaction course: ##STR5## (wherein R₁ and n have the same meaning as defined above; Z is an alkali metal atom; X is a halogen atom; R'₂ is a lower alkyl group).

The compound (I) of this invention is optionally converted in a conventional manner to its pharmaceutically acceptable salt at the nitrogen atom on the dibenzoxazepine ring or at the carboxyl group when R₂ is hydrogen.

The compound (I) of this invention thus prepared has lipid lowering activity, lipid peroxide lowering activity, blood sugar lowering activity and activity to inhibit the aggregation of platelets, and hence is useful as a medicine.

When used as a medicine having these activities, the compound of this invention is formulated by a conventional technique and administered orally in the form of, say, a tablet, granule, powder or capsule, or parenterally in the form of an injection. For preparing a tablet, gradule, powder and capsule, lactose, starch, dextrin, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc and magnesium stearate are preferably used as a pharmaceutical excipient. For preparing an injection, the compound (I) is dissolved in a solution of salt such as sodium bicarbonate or potassium bicarbonate. For oral administration, the dose is 1-2000 mg/day, preferably 5-800 mg/day, and for parenteral administration, the dose is 0.1-500 mg/day, preferably 0.5-200 mg/day, and the desired amount is administered in a single dose or in divided portions.

This invention is now described in greater detail by reference to the following Experiments and Examples to which the invention is by no means limited.

EXPERIMENT 1

Male mice of ddY strain weighing between 25 and 30 g were divided into groups of 10 members each and administered intravenously 75 mg/kg of alloxan. Twenty-two hours later, each mouse was administered orally 300 mg/kg of a test compound of this invention as suspended in 1% gum arabic. Forty-eight hours after the administration of alloxan, blood was drawn from the inferior vena cava under ether anesthesia of the animals with ether. The lipid peroxide level (TBA) of blood was determined with Lipoperoxide-Test Wako (Wako Pure Chemical Industries, Ltd., Japan). The level of blood sugar (BG) was determined with New Blood Sugar Test (Berlinger Mannheim AG., West Germany). The average percent reduction of TBA and BG of the mice treated with the compounds of this invention is set forth in Table 1 on the basis of the values for the untreated mice. As a positive control, tocopherol was used.

                  TABLE 1                                                          ______________________________________                                          ##STR6##                                                                                             Percent                                                                         Reduction                                                                       T B A   B G                                           Compound                 -x ± -x ±                                       No.  R.sub.1  R.sub.2  R.sub.3     S.E.  S.E.                                  ______________________________________                                         α-tocopherol       51.7 ±                                                                              --                                                                     3.7                                                   1    H        H        H           12.3 ±                                                                            15.5 ±                                                                3.2   2.5                                   2    4OCH.sub.3                                                                              H        H           25.5 ±                                                                            22.4 ±                                                                3.5   4.2                                   3    3CH.sub.3                                                                               C.sub.2 H.sub.5                                                                         H           23.0 ±                                                                            16.5 ±                                                                4.1   2.7                                   4    3CH.sub.3                                                                               C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                            35.2 ±                                                                            --                                                                       4.3                                         5    3OCH.sub.3                                                                              C.sub.2 H.sub.5                                                                         CH.sub.3    61.1 ±                                                                            --                                                                       2.5                                         6    3OCH.sub.3                                                                              C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                            54.0 ±                                                                            --                                                                       2.9                                         7    3OCH.sub.3                                                                              H        CH.sub.3    64.8 ±                                                                            15.7 ±                                                                2.2   4.1                                   8    3CH.sub.3                                                                               H        CH.sub.3    52.0 ±                                                                            16.3 ±                                                                3.6   2.6                                   9    3OCH.sub.3                                                                              H        C.sub.2 H.sub.5                                                                            67.7 ±                                                                            18.4 ±                                                                1.8   3.1                                   10   4-OCH.sub.3                                                                             CH.sub.3 H           50.3 ±                                                                            --                                                                       2.5                                         11   4-OCH.sub.3                                                                             C.sub.3 H.sub.7 (n)                                                                     H           38.6 ±                                                                            --                                                                       4.1                                         12   4-OCH.sub.3                                                                             C.sub.4 H.sub.9 (n)                                                                     H           19.7 ±                                                                            --                                                                       3.8                                         13   2-Cl     H        H           18.3 ±                                                                            10.4 ±                                                                4.2   4.6                                   14   4-OC.sub.2 H.sub.5                                                                      H        H           63.4 ±                                                                            18.7 ±                                                                2.1   2.8                                   15   2-CH.sub.3                                                                              H        H           23.8 ±                                                                            16.5 ±                                                                3.5   3.5                                   16   2,4-     C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                            28.5 ±                                                                            --                                         (OCH.sub.3).sub.2             3.1                                         17   2-OCH.sub.3                                                                             C.sub.2 H.sub.5                                                                          ##STR7##   34.4 ± 2.9                                                                        --                                    18   3-OCH.sub.3                                                                             C.sub.2 H.sub.5                                                                          ##STR8##   41.7 ± 3.2                                                                        --                                    19   3-OCH.sub.3                                                                             C.sub.2 H.sub.5                                                                         m-CH.sub.3 C.sub.6 H.sub.4                                                                 34.9 ±                                                                            --                                                                       2.2                                         20   3-CH.sub.3                                                                              C.sub.2 H.sub.5                                                                         C.sub.3 H.sub.7 (n)                                                                        39.6 ±                                                                            --                                                                       3.8                                         ______________________________________                                    

EXPERIMENT 2

The mice of ddY strain weighing between 25 and 30 g were fasted overnight and then Triton WR-1399(500 mg/kg) (Ruger Chemicals Co.) was intravenously injected into the mice. Immediately and 8 hours after the injection, each mouse was administered 150 mg/kg of a test compound of this invention as suspended in 1% aqueous methylcellulose.

24 Hours after the injection of Triton, the blood was drawn from the heart. The cholesterol (TC) and triglyuride (TG) levels of plasma were determined with RaBASuper (Chugai Seiyaku K.K., Japan). The results are shown in Table 2 below.

As a positive control, chlofibrate were used.

                  TABLE 2                                                          ______________________________________                                          ##STR9##                                                                                             Percent                                                                         Reduction                                                                       T C     T G                                           Compound                 -x ± -x ±                                       No.  R.sub.1  R.sub.2  R.sub.3     S.E.  S.E.                                  ______________________________________                                         chlofibrate              13.8 ±                                                                               9.5 ±                                                              3.8     2.5                                           1    H        H        H           19.3 ±                                                                            20.8 ±                                                                2.8   3.7                                   2    4OCH.sub.3                                                                              H        H           21.4 ±                                                                            23.5 ±                                                                4.2   3.3                                   3    3CH.sub.3                                                                               C.sub.2 H.sub.5                                                                         H           17.8 ±                                                                            18.7 ±                                                                3.4   4.5                                   4    3CH.sub.3                                                                               C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                            18.4 ±                                                                            18.7 ±                                                                2.8   3.6                                   5    3OCH.sub.3                                                                              C.sub.2 H.sub.5                                                                         CH.sub.3    20.7 ±                                                                            17.8 ±                                                                7.1   4.4                                   6    3OCH.sub.3                                                                              C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                            19.5 ±                                                                            19.6 ±                                                                4.7   2.8                                   7    3OCH.sub.3                                                                              H        CH.sub.3    17.3 ±                                                                            18.8 ±                                                                2.7   3.3                                   8    3CH.sub.3                                                                               H        CH.sub.3    18.6 ±                                                                            19.3 ±                                                                4.4   2.7                                   9    3OCH.sub.3                                                                              H        C.sub.2 H.sub.5                                                                            17.9 ±                                                                            18.5 ±                                                                3.7   3.4                                   10   4-OCH.sub.3                                                                             CH.sub.3 H           20.7 ±                                                                            24.5 ±                                                                2.8   3.1                                   11   4-OCH.sub.3                                                                             C.sub.3 H.sub.7 (n)                                                                     H           19.2 ±                                                                            21.3 ±                                                                1.9   4.2                                   12   4-OCH.sub.3                                                                             C.sub.4 H.sub.9 (n)                                                                     H           17.4 ±                                                                            19.3 ±                                                                3.2   2.9                                   13   2-Cl     H        H           14.5 ±                                                                            15.2 ±                                                                3.5   4.1                                   14   4-OC.sub.2 H.sub.5                                                                      H        H           19.5 ±                                                                            21.3 ±                                                                4.2   2.5                                   15   2-CH.sub.3                                                                              H        H           17.7 ±                                                                            19.4 ±                                                                3.4   3.8                                   16   2,4-     C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                            16.4 ±                                                                            17.8 ±                                  (OCH.sub.3).sub.2             4.1   2.9                                   17   2-OCH.sub.3                                                                             C.sub.2 H.sub.5                                                                          ##STR10##  17.4 ± 3.5                                                                        19.7 ± 4.5                         18   3-OCH.sub.3                                                                             C.sub.2 H.sub.5                                                                          ##STR11##  18.4 ± 2.9                                                                        21.3 ± 3.2                         19   3-OCH.sub.3                                                                             C.sub.2 H.sub.5                                                                         m-CH.sub.3 C.sub.6 H.sub.4                                                                 20.1 ±                                                                            19.7 ±                                                                4.5   3.6                                   20   3-CH.sub.3                                                                              C.sub.2 H.sub.5                                                                         C.sub.3 H.sub.7 (n)                                                                        16.5 ±                                                                            17.4 ±                                                                3.7   4.1                                   ______________________________________                                    

EXPERIMENT 3

Platelet rich plasma samples were prepared from the blood of SD strain rats, and to 0.5 ml of the samples, test compounds in the form of a solution in dimethyl sulfoxide (DMSO) were added in such an amount that the concentration of the compounds in the mixture was 1×10⁻⁴ M. The assay media containing aspirin were used as a control. After incubation for one minute, arachidonic acid, collagen and adenosine diphosphate (ADP) were added to the mixture in concentrations of 1×10⁻⁴ M, 1.5×10⁻³ M and 1×10⁻⁶ M, respectively, to aggregate the platelets. The aggregation level was determined with an aggregometer. CORNING-EEL MODEL 16P (Manufactured by Evans Electro Selenium Ltd.) and the percent inhibition of platelets was calculated from the following equation: ##EQU1## The results are shown in Table 3 below.

                                      TABLE 3                                      __________________________________________________________________________      ##STR12##                                                                                              Percent Inhibition of                                                          Aggregation (%)                                       Compound                 Arachidonic                                           No.                                                                               R.sub.1                                                                               R.sub.2                                                                             R.sub.3   acid   Collagen                                                                            ADP                                       __________________________________________________________________________     aspirin                  100    8    17                                        1  3CH.sub.3                                                                             C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                          60     47   50                                        2  3OCH.sub.3                                                                            C.sub.2 H.sub.5                                                                     CH.sub.3  63     50   45                                        3  3CH.sub.3                                                                             C.sub.2 H.sub.5                                                                     CH.sub.3  55     43   50                                        4  4CH.sub.3                                                                             C.sub.2 H.sub.5                                                                     CH.sub.3  60     48   51                                        5  4OCH.sub.3                                                                            C.sub.2 H.sub.5                                                                     CH.sub.3  45     30   35                                        6  4OCH.sub.3                                                                            C.sub.2 H.sub.5                                                                     H         40     25   20                                        7  4OCH.sub.3                                                                            CH.sub.3                                                                            H         38     34   36                                        8  4OCH.sub.3                                                                            C.sub.3 H.sub.7                                                                     H         42     40   43                                        9  4OCH.sub.3                                                                            C.sub.4 H.sub.9                                                                     H         43     37   35                                        10 2,4-(OCH.sub.3).sub.2                                                                 C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                          52     47   44                                        11 2-OCH.sub.3                                                                           C.sub.2 H.sub.5                                                                      ##STR13##                                                                               48     45   46                                        12 3OCH.sub.3                                                                            C.sub.2 H.sub.5                                                                      ##STR14##                                                                               50     43   40                                        13 3OCH.sub.3                                                                            C.sub.2 H.sub.5                                                                     m-CH.sub.3.C.sub.6 H.sub.4                                                               45     41   39                                        14 3CH.sub.3                                                                             C.sub.2 H.sub.5                                                                     C.sub.3 H.sub.7                                                                          60     50   47                                        __________________________________________________________________________

EXPERIMENT 4

A solution of a test compound (5×10⁻⁴ M) was added to one ml of a mixture consisting of 0.9 mg of pig aortic microsomes and 9×10⁸ platelets of SD strain rats. To the mixture, 10 μl of (1-14_(C))k-arachidonic acid (80 nM, 4.7 Ci/mol) in 0.1 M sodium bicarbonate aqueous solution was added, and after a 3 minutes' reaction at 23° C., 50 μl of 0.5 M citric acid aqueous solution was added to terminate the reaction. To the reaction mixture, 8 ml of ethyl acetate was added and shaked. The organic layer was concentrated to dryness under vacuum, and the residue was dissolved in 100 μl of ethyl acetate, and the solution was subjected to thin-layer chromatography using a silica gel glass plate and a developing solvent made of the upper phase of a 5:11:2:10 mixture of iso-octane/ethyl acetate/acetic adic/water.

After completion of the development, the plate was scanned for radioactivity, and the silica gel in the areas corresponding to radioactive bands of thromboxane B₂ and 6-keto-prostaglandin F₁α was scrapped and its radioactivity was determined with a liquid scintillation counter. The percent conversion of arachidonic acid to thromboxane B₂ or to 6-keto-prostaglandin F₁α was calculated, and the amount each of thromboxane B₂ and 6-keto-prostaglandin F₁α was determined.

Under the conditions described above, all of the TXA₂ and PGI₂ appeared to be converted into TXB₂ and 6-keto-PGF₁α, respectively. Thus, it can be assumed that the amounts of TXB₂ and 6-keto-PGF₁α were equated with those of TXA₂ and PGI₂ formed in the reaction system.

The results are shown in Table 4 wherein the data are based on the amounts of thromboxane B₂ and 6-ketoprostaglandin F₁α in samples not containing the test compounds. As controls, samples containing imidazole and aspirin were used.

                  TABLE 4                                                          ______________________________________                                          ##STR15##                                                                                    Percent Relative                                                                            Percent Relative                                   Compound       Production of                                                                               Production of                                      No.  R.sub.1  R.sub.2                                                                              R.sub.3                                                                             PGI.sub.2  TXA.sub.2                                  ______________________________________                                         imidazole      3.0          0.25                                               aspirin        0.1          0.1                                                1    4OCH.sub.3                                                                              H     H    1.5        0.1                                        2    H        H     H    1.3        0.1                                        3    3OCH.sub.3                                                                              H     CH.sub.3                                                                            3.5        0.35                                       4    3CH.sub.3                                                                               H     C.sub.2 H.sub.5                                                                     7.0        0.25                                       5    3CH.sub.3                                                                               H     CH.sub.3                                                                            4.7        0.45                                       6    3OCH.sub.3                                                                              H     C.sub.2 H.sub.5                                                                     3.7        0.3                                        7    2-Cl     H     H    1.8        0.15                                       8    4OC.sub.2 H.sub.5                                                                       H     H    2.5        0.2                                        9    2CH.sub.3                                                                               H     H    3.1        0.35                                       ______________________________________                                    

EXAMPLE 1

A solution of 1 g of ethyl 10,11-dihydro-4-methoxylbenz[b,f][1,4]oxazepine-8-carboxylate in 30 ml of chloroform was irradiated with natural light for 10 days, and the solvent was distilled off. The residue was subjected to chromatography on silica gel to give 0.85 g of ethyl 4-methoxybenz[b,f][1,4]oxazepine-8-carboxylate. m.p. 95°-96° C.

Elemental analysis: Calculated for C₁₇ H₁₅ NO₄ : 68.68 C, 5.09 H, 4.71 N(%); Found: 68.78 C, 5.17 H, 4.82 N(%).

EXAMPLE 2

A mixture of 2 g of ethyl 10,11-dihydro-4-methoxydibenz-[b,f][1,4]oxazepine-8-carboxylate, 2 g of chloranil and 30 ml of xylene was refluxed for 3 hours, and the solvent was distilled off under vacuum. The residue was subjected to chromatography on silica gel to give 1.8 g of ethyl 4-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate. The melting point and elemental analysis of the product were the same as those of a mixture with the product obtained in Example 1.

EXAMPLE 3

The compounds indicated in Table 4 were prepared by repeating the procedures of Examples 1 and 2. The yield data in the Table are those for the products produced by the procedure of Example 1, and similar data were obtained when the procedure of Example 2 was followed. Since the compounds identified as Nos. 9 and 10 were obtained as an oily product, the values for high-resolution mass spectrophotometry are indicated in the column "Elemental analysis" of Table 5, with the values for proton NMR being indicated as footnotes.

                                      TABLE 5                                      __________________________________________________________________________      ##STR16##                                                                      Substituent and its               Elemental Analysis                          position        Molecular                                                                             Yield                                                                              m.p.    Calculated (%)                                                                          Found (%)                          No.                                                                               R.sub.1                                                                             R.sub.2 Formula                                                                               (%) (°C.)                                                                           C  H  N  C  H    N                          __________________________________________________________________________     1  H    8-CO.sub.2 C.sub.2 H.sub.5                                                             C.sub.16 H.sub.13 NO.sub.3                                                            87  119-121 71.90                                                                             4.90                                                                              5.24                                                                              71.79                                                                             4.94 5.20                       2  3-OCH.sub.3                                                                         "       C.sub.17 H.sub.15 NO.sub.4                                                            95  107-109 68.68                                                                             5.09                                                                              4.71                                                                              68.63                                                                             5.17 4.82                       3  2-OCH.sub.3                                                                         "       C.sub.17 H.sub.15 NO.sub.4                                                            93  132-132.5                                                                              68.68                                                                             5.09                                                                              4.71                                                                              68.71                                                                             5.22 4.82                       4  4-OC.sub.2 H.sub.5                                                                  "       C.sub.18 H.sub.17 NO.sub.4                                                            85   72-73  69.44                                                                             5.50                                                                              4.50                                                                              69.62                                                                             5.64 4.58                       5  2-CH.sub.3                                                                          "       C.sub.17 H.sub.15 NO.sub.3                                                            84  126-127.5                                                                              72.58                                                                             5.37                                                                              4.98                                                                              72.86                                                                             5.48 5.16                       6  2-Cl "       C.sub.16 H.sub.12 ClO.sub.3                                                           86  118-120 63.69                                                                             4.01                                                                              4.64                                                                              63.58                                                                             4.17 4.79                       7  4-OCH.sub.3                                                                         8-CO.sub.2 CH.sub.3                                                                    C.sub.16 H.sub.13 NO.sub.4                                                            82  164-165 67.84                                                                             4.63                                                                              4.94                                                                              67.76                                                                             4.51 5.02                       8  4-OC.sub.2 H.sub.5                                                                  "       C.sub.17 H.sub.15 NO.sub.4                                                            87  125     68.68                                                                             5.09                                                                              4.71                                                                              68.73                                                                             5.15 4.84                       9  4-OCH.sub.3                                                                         8-CO.sub.2 C.sub.3 H.sub.7 (n)                                                         C.sub.18 H.sub.17 NO.sub.4                                                            90  oil     311.1153 mass spectrum*.sup.1                                                           311.1162                           10 4-OCH.sub.3                                                                         8-CO.sub.2 C.sub.4 H.sub.9 (n)                                                         C.sub.19 H.sub.19 NO.sub.4                                                            89  oil     325.1309 high mass spectrum*.sup.2                                                      325.1320                           11 4-OCH.sub.3                                                                         8-CO.sub.2 H                                                                           C.sub.15 H.sub.11 NO.sub.4                                                            63  280     66.91                                                                             4.12                                                                              5.20                                                                              67.09                                                                             4.07 5.16                                                  (decomposition)                                     __________________________________________________________________________      *.sup.1 NMR(CDCl.sub. 3) δ :8.55(1H,S,11 H), 6.75-8.15(6H,               aromaticH), 4.25(2H,t,J = 6Hz, CO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3),           3.85(3H,S,OCH.sub.3), 1.75(2H, sextet,J = 6Hz, CO.sub.2 CH.sub.2 CH.sub.2      CH.sub.3), 1.0(3H,t,J = 6Hz, CO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3)              *.sup.2 NMR(CDCl.sub.3) δ: 8.55(1H,S,11 H), 6.80-8.10(6H, aromaticH      4.30(2H,t,J = 6Hz,CO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3),               3.85(3H,S,OCH.sub.3),                                                          2.0-0.80(7H,br,CO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3)             

EXAMPLE 4

A mixture of 8.3 g of ethyl 3-acetylamino-4-(3-methoxyphenoxy)-benzoate and 15.4 g of phosphorus oxychloride and 50 ml of dried toluene was refluxed for 3 hours. The mixture was then cooled and the precipitating crystal was filtered and washed with ethyl acetate to give 8.2 g of ethyl 11-methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate hydrochloride. The product was neutralized with ammonia water and extracted with ethyl acetate. After concentrating the extract, ethanol was added to the residue and the precipitating crystal was recrystallized from ethanol to give 6.9 g of ethyl 11-methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate as a colorless acicular crystal.

Yield 88%, m.p. 117°-118° C.

Elemental analysis: Calculated for C₁₈ H₁₇ NO₄ : 69.44 C, 5.50 H, 4.50 N(%); Found: 69.48 C, 5.56 H, 4.43N(%).

The compounds indicated in Tables 6 and 7 were produced by repeating the same procedure as above.

                                      TABLE 6                                      __________________________________________________________________________      ##STR17##                                                                     Substituent and its              Elemental Analysis                            position          Molecular                                                                            Yield                                                                              m.p. Calculated (%)                                                                         Found (%)                             No.                                                                               R.sub.1                                                                               R.sub.2 Formula                                                                              (%) (°C.)                                                                        C H  N   C  H  N                              __________________________________________________________________________      1 2-OCH.sub.3                                                                           CH.sub.3                                                                               C.sub.18 H.sub.17 NO.sub.4                                                           65  130-131                                                                             69.44                                                                             5.50                                                                              4.50                                                                              69.39                                                                             5.52                                                                              4.43                            2 3-OCH.sub.3                                                                           C.sub.2 H.sub.5                                                                        C.sub.19 H.sub.19 NO.sub.4                                                           93    61-62.5                                                                           70.14                                                                             5.89                                                                              4.30                                                                              70.10                                                                             5.82                                                                              4.33                            3 2-OCH.sub.3                                                                           C.sub.6 H.sub.5                                                                        C.sub.23 H.sub.19 NO.sub.4                                                           80  102-103                                                                             73.98                                                                             5.13                                                                              3.75                                                                              73.97                                                                             5.11                                                                              3.68                            4 3-OCH.sub.3                                                                           "       "     95  132-133 "     73.89                                                                             5.15                                                                              3.69                            5 4-OCH.sub.3                                                                           "       "     70  155-156 "     73.90                                                                             5.12                                                                              3.73                            6 2-OCH.sub.3                                                                           CHCHC.sub.6 H.sub.5                                                                    C.sub.25 H.sub.21 NO.sub.4                                                           68  120-130                                                                             75.17                                                                             5.30                                                                              3.51                                                                              75.15                                                                             5.20                                                                              3.48                            7 3-OCH.sub.3                                                                           "       "     71  120.5-121.5                                                                            "     75.21                                                                             5.25                                                                              3.42                            8 4-OCH.sub.3                                                                           "       "     53  87-89   "     75.20                                                                             5.38                                                                              3.39                            9 3-OCH.sub.3                                                                           m-CH.sub.3 C.sub.6 H.sub.4                                                             C.sub.24 H.sub.21 NO.sub.4                                                           93  172.5-173.5                                                                         74.40                                                                             5.46                                                                              3.62                                                                              74.36                                                                             5.48                                                                              3.60                           10 4-OCH.sub.3                                                                           "       "     81  179-180 "     74.36                                                                             5.45                                                                              3.59                           11 2,4-(OCH.sub.3).sub.2                                                                 C.sub.2 H.sub.5                                                                        C.sub.20 H.sub.21 NO.sub.5                                                           88  133-135                                                                             67.59                                                                             5.96                                                                              3.94                                                                              67.63                                                                             5.90                                                                              3.88                           12 "      C.sub.6 H.sub.5                                                                        C.sub.24 H.sub.21 NO.sub.5                                                           92  137-138                                                                             71.45                                                                             5.25                                                                              3.47                                                                              71.40                                                                             5.23                                                                              3.45                           13 3-CH.sub.3                                                                            CH.sub.3                                                                               C.sub.18 H.sub.17 NO.sub.3                                                           75  111-112                                                                             73.20                                                                             5.80                                                                              4.74                                                                              73.13                                                                             5.76                                                                              4.71                           14 3-CH.sub.3                                                                            C.sub.2 H.sub.5                                                                        C.sub.19 H.sub.19 NO.sub.3                                                           79   41-43                                                                              73.77                                                                             6.19                                                                              4.53                                                                              73.72                                                                             6.18                                                                              4.45                           15 4-CH.sub.3                                                                            "       C.sub.19 H.sub.20 ClNO.sub.3                                                         62  115-117                                                                             65.99                                                                             5.83                                                                              4.05                                                                              65.90                                                                             5.90                                                                              4.01                           16 3-CH.sub.3                                                                            n-C.sub.3 H.sub.7                                                                      C.sub.20 H.sub.22 ClNO.sub.3                                                         73  139-141                                                                             66.75                                                                             6.16                                                                              3.89                                                                              66.73                                                                             6.20                                                                              3.81                           17 2-CH.sub.3                                                                            C.sub.6 H.sub.5                                                                        C.sub.23 H.sub.19 NO.sub.3                                                           67  104-106                                                                             77.29                                                                             5.36                                                                              3.92                                                                              77.35                                                                             5.37                                                                              3.87                           18 3-CH.sub.3                                                                            C.sub.6 H.sub.5                                                                        C.sub.23 H.sub.19 NO.sub.3                                                           88  139-140                                                                             77.29                                                                             5.36                                                                              3.92                                                                              77.24                                                                             5.35                                                                              3.85                           19 4-CH.sub.3                                                                            "       "     85  135-136 "     77.30                                                                             5.33                                                                              3.87                           20 2-CH.sub.3                                                                            m-CH.sub.3 C.sub.6 H.sub.4                                                             C.sub.24 H.sub.21 NO.sub.3                                                           82  128-129                                                                             77.61                                                                             5.70                                                                              3.77                                                                              77.49                                                                             5.75                                                                              3.71                           __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________      ##STR18##                                                                     Substituent and                Elemental Analysis                              its position    Molecular                                                                            Yield                                                                              m.p. Calculated (%)                                                                          Found (%)                              No.                                                                               R.sub.1                                                                             R.sub.2 Formula                                                                              (%) (°C.)                                                                        C  H  N  C  H  N                                __________________________________________________________________________     1  3-OCH.sub.3                                                                         C.sub.2 H.sub.5                                                                        C.sub.19 H.sub.19 NO.sub.4                                                           81  191-192                                                                             60.95                                                                             5.39                                                                              3.74                                                                              60.77                                                                             5.28                                                                              3.54                                             1/2 H.sub.2 SO.sub.4                                           2  3-OCH.sub.3                                                                         p-CH.sub.3C.sub.6 H.sub.4                                                              C.sub.24 H.sub.21 NO.sub.4                                                           90  111-112                                                                             74.40                                                                             5.64                                                                              3.62                                                                              74.32                                                                             5.51                                                                              3.47                             __________________________________________________________________________

EXAMPLE 5

A mixture of 1 g of ethyl 11-methyl-3-methoxydibenz-[b,f][1,4]oxazepine-8-carboxylate, 10 ml of methanol and 10 ml of 1 N aqueous sodium hydroxide was refluxed for 1 hour. After cooling, the mixture was neutralized with diluted hydrochloric acid, and the precipitating crystal was filtered off and recrystallized from methanol to give 0.84 g of 11-methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylic acid. Yield 92%, m.p. 247° C. (with decomposition).

Elemental analysis: Calculated for C₁₆ H₁₃ NO₄ : 67.84 C. 4.63 H, 4.94 N(%); Found: 67.82 C, 4.61 H, 4.90 N(%).

The compounds indicated in Table 8 were prepared by repeating the same procedure as above.

                                      TABLE 7                                      __________________________________________________________________________      ##STR19##                                                                     Substituent and its               Elemental Analysis                           position        Molecular                                                                            Yield                                                                              m.p.    Calculated (%)                                                                          Found (%)                           No.                                                                               R.sub.1                                                                             R.sub.2 Formula                                                                              (%) (°C.)                                                                           C  H  N  C  H  N                             __________________________________________________________________________     1  4-OCH.sub.3                                                                         m-CH.sub.3 C.sub.6 H.sub.4                                                             C.sub.22 H.sub.17 NO.sub.4                                                           91  246-247 73.57                                                                             4.77                                                                              3.90                                                                              73.48                                                                             4.70                                                                              3.83                          2  4-CH.sub.3                                                                          C.sub.6 H.sub.5                                                                        C.sub.21 H.sub.15 NO.sub.3                                                           92  275-277 76.58                                                                             4.59                                                                              4.25                                                                              76.60                                                                             4.65                                                                              4.20                          3  3-OCH.sub.3                                                                         C.sub.2 H.sub.5                                                                        C.sub.17 H.sub.15 NO.sub.4                                                           90  248-250 68.68                                                                             5.09                                                                              4.71                                                                              68.59                                                                             5.05                                                                              4.76                          4   "   m-CH.sub.3 C.sub.6 H.sub.4                                                             C.sub.22 H.sub.17 NO.sub.4                                                           95  229-230 76.07                                                                             4.93                                                                              4.03                                                                              76.01                                                                             4.93                                                                              4.00                          5   "   CHCHC.sub.6 H.sub.5                                                                    C.sub.23 H.sub.17 NO.sub.4                                                           93  250     74.38                                                                             4.61                                                                              3.77                                                                              74.31                                                                             4.50                                                                              3.72                                                    (decomposition)                                      6  3-CH.sub.3                                                                          CH.sub.3                                                                               C.sub.16 H.sub.13 NO.sub.3                                                           93  230-232 71.90                                                                             4.90                                                                              5.24                                                                              71.89                                                                             4.95                                                                              5.19                          7  3-CH.sub.3                                                                          C.sub.2 H.sub.5                                                                        C.sub.17 H.sub.15 NO.sub.3                                                           90  211-213 72.58                                                                             5.37                                                                              4.98                                                                              72.53                                                                             5.38                                                                              4.89                          __________________________________________________________________________ 

What is claimed is:
 1. A dibenzoxazepine derivative of the formula: ##STR20## wherein the carboxy substituent is in the 6- or 8-position; R₁ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; n is an integer of 1 or 2 provided that each R₁ is the same or different when n is 2; R₂ is a hydrogen atom or a lower alkyl group; R₃ is a lower alkyl group, a phenyl group which may have a m-CH₃ group substituent or a styryl group; or a pharmaceutically acceptable salt thereof.
 2. A dibenzoxazepine derivative of the formula: ##STR21## wherein R₁ is a lower alkyl group or a lower alkoxyl group; R₂ is a hydrogen atom or a lower alkyl group; R₃ is a lower alkyl group or a pharmaceutically acceptable salt thereof.
 3. A dibenzoxazepine derivative of the formula: ##STR22## wherein R₁ is methyl or methoxy; R₂ is a hydrogen atom, methyl or ethyl; R₃ is methyl or ethyl; or a pharmaceutically acceptable salt thereof.
 4. 11-Ethyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylic acid according to claim
 2. 5. Ethyl 11-methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate according to claim
 2. 6. 3,11-Dimethyldibenz[b,f][1,4]oxazepine-8-carboxylic acid according to claim
 2. 7. Ethyl 3,11-dimethyldibenz[b,f][1,4]oxazepine-8-carboxylate according to claim
 2. 8. 11-Methyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylic acid according to claim
 2. 9. Ethyl 11-ethyl-3-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate according to claim
 2. 10. 11-Ethyl-3-methyldibenz[b,f][1,4]oxazepine-8-carboxylic acid according to claim
 2. 11. Ethyl 11-ethyl-3-methyldibenz[b,f][1,4]oxazepine-8-carboxylate according to claim
 2. 12. Ethyl 11-n-propyl-3-methyldibenz[b,f][1,4]oxazepine-8-carboxylate according to claim
 2. 13. A pharmaceutical composition for treating diseases in circulatory organs comprising a dibenzoxzepine derivative of the formula: ##STR23## wherein the carboxy group is in the 6- or 8-position; R₁ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group; n is an integer of 1 or 2 provided that each R₁ may be different when n is 2; R₂ is a hydrogen atom or a lower alkyl group; R₃ is, a lower alkyl group, a phenyl group which may have a m-CH₃ group as substituent or a styryl group; or a pharmaceutically acceptable excipient.
 14. A composition according to claim 13 which is formulated in the form of a tablet, granule, powder or capsule suitable for oral administration.
 15. A composition according to claim 14 which contains as an excipient lactose, starch, dextrin, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc or magnesium stearate.
 16. A composition according to claim 13 which is formulated in a form suitable for injection.
 17. A composition according to claim 16 which contains as a diluent a salt solution selected from the group consisting of aqueous solution bicarbonate and aqueous potassium bicarbonate.
 18. A method for treating diseases in circulatory organs which comprises administering to a patient in need of said therapy an amount effective for said therapy of a compound according to claim
 1. 19. A method according to claim 18, wherein the composition is administered in an amount of from 1 to 2,000 mg per day of the pharmaceutically active compound.
 20. A method according to claim 18, wherein the composition is administered in an amount of from 5 to 800 mg per day of the pharmaceutically active compound. 